A Phase I/II Study of Infusional Vinblastine with the P-Glycoprotein Antagonist Valspodar (PSC 833) in Renal Cell Carcinoma

Bates, Susan E.; Bakke, Susan; Kang, Min H.; Robey, Robert W.; Zhai, Suoping; Thambi, Paul; Chen, Clara C.; Patil, Sheela; Smith, Tom; Steinberg, Seth M.; Mj, Merino; Goldspiel, Barry R.; Meadows, Beverly; Stein, Wilfred D.; Choyke, Peter; Balis, Frank M.; Figg, William D.; Fojo, Tito

doi:10.1158/1078-0432.ccr-0829-03

Cited by 67 publications

(54 citation statements)

References 27 publications

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“…However, three patients (Patients #7, 9, and 11) who had no residual plasma doxorubicin prior to their second cycle, all consistently had 50% reduction in total doxorubicin clearance in cycle 2 supporting the conclusion that this finding was not an estimation artefact from the residual drug. Therefore, the reduction in total doxorubicin clearance with the addition of valspodar in cycle 2 was likely a result of a pharmacokinetic interaction, similar to that seen in other models where the clearance of single agent cytotoxic agents such as etoposide, doxorubicin, paclitaxel, and vinblastine was significantly reduced by valspodar administration (Boote et al, 1996;Giaccone et al, 1997;Fracasso et al, 2000;Bates et al, 2001Bates et al, , 2004Chico et al, 2001;Minami et al, 2001). An influence of repeated administrations of PEG-LD on this interaction could not be assessed, as all patients received valspodar in combination with PEG-LD after cycle 1.…”

Section: Discussionsupporting

confidence: 60%

“…Clinical trials in solid tumour malignancies using the P-glycoprotein modulator, valspodar, combined with single agent etoposide, doxorubicin, paclitaxel, or vinblastine have required dose reductions of the antineoplastic agents (Boote et al, 1996;Giaccone et al, 1997;Fracasso et al, 2000;Bates et al, 2001Bates et al, , 2004Chico et al, 2001;Minami et al, 2001). These dose reductions are necessary in order to reduce toxicity due to the decreased clearance and increased AUC of these agents when given in combination with valspodar.…”

Section: Discussionmentioning

confidence: 99%

“…One such agent, valspodar (PSC 833), a cyclosporine D analogue, reverses P-glycoprotein-mediated resistance in vitro at concentrations of 1000 ng ml À1 (Twentyman and Bleehen, 1991). In phase 1 studies, combinations of valspodar with single agent etoposide, doxorubicin, paclitaxel, or vinblastine are feasible with toxicities consisting of reversible cerebellar ataxia, myelosuppression, and hyperbilirubinemia (Boote et al, 1996;Giaccone et al, 1997;Fracasso et al, 2000;Bates et al, 2001Bates et al, , 2004Chico et al, 2001;Minami et al, 2001). Responses and disease stabilisation have been noted in patients with carcinomas of the ovary, lung, and kidney (Fracasso et al, 2000;Bates et al, 2001;Chico et al, 2001).…”

mentioning

confidence: 99%

“…Valspodar has been shown to decrease the clearance of etoposide, doxorubicin, paclitaxel, and vinblastine, and these interactions have necessitated dose reductions of the anticancer agents when given as single agents in combination with valspodar (Boote et al, 1996;Giaccone et al, 1997;Fracasso et al, 2000;Bates et al, 2001Bates et al, , 2004Chico et al, 2001;Minami et al, 2001). Liposomal encapsulated anticancer agents may be better suited to combination therapy with valspodar therapy, as one such agent, liposomal doxorubicin, appears to have minimal pharmacokinetic interactions with valspodar in mice, in comparison to free doxorubicin (Krishna and Mayer, 1997;Krishna et al, 2000).…”

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confidence: 99%

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Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

Fracasso¹,

Blum²,

K.³

et al. 2005

Br J Cancer

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Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20 -25 mg m À2 intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m À2 and escalated in an accelerated titration design to 25 mg m À2 . Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m À2 . The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10 -73) ml h À1 m À2 in cycle 1 to 18 (3 -37) ml h À1 m À2 with the addition of valspodar in cycle 2 (P ¼ 0.009). Treatment with PEG-LD 25 mg m À2 in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

Fracasso¹,

Blum²,

K.³

et al. 2005

Br J Cancer

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“…The results of the current study may explain the mechanisms of camptothecin analog resistance in some neuroblastomas. (169,170,171).…”

Section: Discussionmentioning

confidence: 99%

The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan

Turner¹

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Clinton Stewart for his guidance and support. I will always appreciate his patience, the numerous opportunities he has provided, and all of the time he has spent teaching me. iii Abstract High-risk neuroblastoma presents a significant therapeutic challenge because the 5-year survival rate remains less than 30% despite the use of surgery, multi-agent chemotherapy, radiation, and autologous bone marrow transplant. Novel therapeutic modalities are under development. The camptothecin analogs topotecan and irinotecan have been identified as successful cytotoxic agents. For topotecan, pharmacokinetically guided dosing to achieve a systemic exposure associated with preclinical anti-tumor activity in neuroblastoma xenograft models is feasible and has elicited favorable responses in children with high-risk neuroblastoma. However, some children with highrisk disease did not respond to the putatively effective topotecan systemic exposure.These children represent a subset of the disease intrinsically resistant to topotecan.Furthermore, mRNA expression of the adenosine triphosphate (ATP)-binding cassette (ABC) transporters P-glycoprotein (Pgp) and multidrug resistance associated protein 1 (MRP1), which efflux many drugs used in neuroblastoma therapy, has been implicated in poor outcome in neuroblastoma. Therefore, the purpose of our studies was to determine the role of ABC transport protein expression in neuroblastoma resistance to the camptothecin analogs topotecan and irinotecan. The results of the in vitro studies demonstrate that MRP4 and Pgp confer resistance to topotecan and SN-38. In the xenograft studies, MRP4 expression was associated with failure to respond to topotecan. However, this phenotype was not recapitulated in children treated with topotecan. These results may be confounded by small sample size and timing of sample acquisition. Further investigation of the role of ABC transporters in children with neuroblastoma who receive either topotecan or irinotecan may be warranted. In addition to the camptothecin analogs, patients will receive other drugs effluxed by the ABC transporters (e.g., doxorubicin, vincristine, etoposide, and cyclophosphamide). Therefore, analyzing ABC transporter expression by immunohistochemistry in diagnostic tumor specimens may help to select agents not subject to efflux by ABC transporters expressed in the tumor. However, eliminating drugs effluxed by ABC transporters from the treatment regimen creates a potential gap in therapy and may reduce drug intensity. Therefore, further rational design and development of drugs that evade ABC transporter-mediated efflux, and potentially other resistance mechanisms in neuroblastoma, is also warranted.

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Multidrug Resistance Reversal in Solid Tumors

Богуш

Robert

2009

ABC Transporters and Multidrug Resistance

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A Phase I/II Study of Infusional Vinblastine with the P-Glycoprotein Antagonist Valspodar (PSC 833) in Renal Cell Carcinoma

Cited by 67 publications

References 27 publications

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan

Multidrug Resistance Reversal in Solid Tumors

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